It is our overall aim to determine the relative contributions of chemoreceptor vs. mechanical vs. metabolic vs. neurophysiologic "state"-related influences on the control of breathing in specific acute and chronic physiologic states in unanesthetized animals and humans. To this end, four areas of research are proposed, each devoted to a specific problem and one or more physiologic states. 1. What is the relative contribution of changes in cerebral fluid (H+) to eupnea in the presence of other chemoreceptor and non-chemoreceptor stimuli and inhibitors? Awake and anesthetized goat preparations will be used which permit differential effects to be imposed separately in the same animal on medullary chemoreception (via cerebral perfusion) and on carotid chemoreceptors (via isolated carotid perfusion). 2. How does physiologic sleep alter the effects of chemical and mechanical influences on the regulation of breathing--particularly the rhythmicity of breathing pattern? Unanesthetized humans and goats will be used to determine the relative roles of chemical stimuli and cerebral hypoxia in inducing periodic breathing and the effects of changes in pulmonary mechanics on inspiratory effort and respiratory muscle recruitment during sleep. 3. How do respiratory muscles adapt to heavy muscular exercise--mechanically and metabolically; and does the nature of this adaptation present a significant constraint to the accompanying ventilatory response? Exercise effects on pulmonary and chest wall mechanics and pressure development will be determined in healthy humans; and exercise effects on metabolism of the respiratory muscles will be assessed in rats. 4. How does the chronic ventilatory response to progesterone affect chest wall mechanics in patients with airway obstruction and chronic CO2 retention? Is the ventilatory response mediated (in guinea pigs and/or rats) by the action of specific metabolites of progesterone in neuroendocrine tissue?...and/or does progesterone exert effects on CNS serotonin metabolism which in turn effect ventilatory regulation? 5. What are the anatomical sites in the CNS and/or spinal cord of the serotonin-mediated nerve transmission involved in the regulation of breathing?